ABSTRACT Exercise Intervention for Smoking Cigarette smoking is the leading cause of death and disability in the United States (U.S.), contributing to over 440,000 deaths each year. Still, over 40 million adults in the U.S. currently smoke despite well-established links to morbidity and mortality. Empirical evidence suggests that quitting smoking may be particularly difficult for smokers with certain types of psychological vulnerability. Although panic and related anxiety problems frequently co-occur with smoking, there has been very little attention applied to improving cessation outcome among this high-risk group of smokers. This neglect sits on the backdrop of a larger issue in the smoking cessation literature: a general lack of innovation in efficacious psychosocial treatments for nicotine dependence. Researchers have frequently called attention to the links across smoking and anxiety-related states, and recent evidence suggests that panic and related anxiety vulnerability factors, specifically anxiety sensitivity (AS or fear of somatic arousal), negatively impact cessation. Collectively, these findings indicate that there is clinical and theoretical merit to targeting AS among smokers to improve cessation outcome. A growing body of work, including our pilot work conducted over the past number of years, suggests that AS can be effectively treated with exercise. Accordingly, we are proposing a 4-year study to systematically assess the efficacy of exercise augmentation of standard treatment for smoking cessation among anxiety vulnerable smokers. The study comprises a randomized controlled trial comparing the short-term and long-term benefits of cognitive behavioral treatment and nicotine replacement therapy that includes an exercise intervention with the same protocol that includes a contact control intervention. Importantly, the study also will offer novel insight into the putative mechanisms of exercise efficacy. This information is directly relevant to the present smoking population, but also will be a useful theoretical guide for other exercise-substance use disorder work in the future. We will randomize a total of 150 participants with the identical protocol followed at two sites to help ensure the timely recruitment of adequate numbers of participants. This study represents a crucial and important stage in translating basic research to strategies for treating nicotine dependence. This study addresses an important public health issue by assessing an intervention that may lead to a more effective application for the treatment of at-risk smokers. The expected findings should: (1) Guide advances in the theoretical conceptualization of the mechanisms involved in anxiety-exercise-smoking relations. (2) Directly inform the development of a novel and psychosocial/behavioral and pharmacological smoking cessation intervention(s) for smokers with anxiety-related risk factors. (3) Offer a novel and integrative methodological paradigm to the study of the role of exercise in anxiety-smoking relations. The proposed research project also is an interdisciplinary endeavor, involving collaboration across disciplines: between clinical psychologists, psychiatrists, physicians, smoking cessation and mental health counselors. This collaborative interdisciplinary model has proved highly effective in our past related research; we believe it is likely to continue to be highly relevant to the success and broad-based dissemination of the proposed project.